FOXP2 expression and gray matter density in the male brains of patients with schizophrenia

Julio Sanjuán,Luis Martí-Bonmatí,Juan Nacher,J Javier Meana,Javier González-Fernández,Roberto Sanz-Requena,María Dolores Moltó,Noelia Sebastiá-Ortega,Javier Gilabert-Juan,Josep María Haro,Xochitl Helga Castro-Martínez,Gracián García-Martí

doi:10.1007/s11682-020-00339-x

Abstract

Common genetic variants of FOXP2 may contribute to schizophrenia vulnerability, but controversial results have been reported for this proposal. Here we evaluated the potential impact of the common FOXP2 rs2396753 polymorphism in schizophrenia. It was previously reported to be part of a risk haplotype for this disease and to have significant effects on gray matter concentration in the patients. We undertook the first examination into whether rs2396753 affects the brain expression of FOXP2 and a replication study of earlier neuroimaging findings of the influence of this genetic variant on brain structure. FOXP2 expression levels were measured in postmortem prefrontal cortex samples of 84 male subjects (48 patients and 36 controls) from the CIBERSAM Brain and the Stanley Foundation Array Collections. High-resolution anatomical magnetic resonance imaging was performed on 79 male subjects (61 patients, 18 controls) using optimized voxel-based morphometry. We found differences in FOXP2 expression and brain morphometry depending on the rs2396753, relating low FOXP2 mRNA levels with reduction of gray matter density. We detected an interaction between rs2396753 and the clinical groups, showing that heterozygous patients for this polymorphism have gray matter density decrease and low FOXP2 expression comparing with the heterozygous controls. This study shows the importance of independent replication of neuroimaging genetic studies of FOXP2 as a candidate gene in schizophrenia. Furthermore, our results suggest that the FOXP2 rs2396753 affects mRNA levels, thus providing new knowledge about its significance as a potential susceptibility polymorphism in schizophrenia.

Highlights

The forkhead box P2 (FOXP2) gene was identified as the first gene involved in the development of speech and language (Lai et al 2001)
We executed a double approach for examining the relevance of the common FOXP2 rs2396753 in schizophrenia: FOXP2 expression was measured in postmortem human brain tissues from the prefrontal cortex (PFC); Magnetic resonance imaging (MRI) was performed on 79 unrelated subjects recruited as part of a larger research program on schizophrenia
We found a clear concordance between FOXP2 expression and gray matter (GM) density in the brain regarding rs2396753

Summary

Introduction

The forkhead box P2 (FOXP2) gene was identified as the first gene involved in the development of speech and language (Lai et al 2001). Language impairment and speech disorganization are core phenomenological characteristics of patients with schizophrenia; deficits in the neural organization of language were proposed to affect these patients (DeLisi 2001) This observation has led to the suggestion of FOXP2 as a potential candidate gene for schizophrenia vulnerability. We found that the common FOXP2 rs2396753 single nucleotide polymorphism (SNP) might be involved in language disorder vulnerability, including thought disorders and auditory hallucinations in schizophrenia (Sanjuan et al 2006). These symptoms are related with structural, functional and connectivity alterations in brain pathways for language processing (Li et al 2009). A common FOXP2 SNP was nominally associated with phonemic verbal fluency in the Western Australian Family Study of Schizophrenia (McCarthy et al 2019)

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Results

Conclusion